Bioerodible polyorthoesters from dioxolane-based diketene acetals

ABSTRACT

Bioerodible polyorthoesters useful as orthopedic implants or vehicles for the sustained delivery of pharmaceutical, cosmetic and agricultural agents contain hydrogen bonding groups and α-hydroxy acid-containing groups.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This application relates to polyorthoesters. In particular, thisinvention relates to bioerodible polyorthoesters containing new diketeneacetals and α-hydroxy acid-containing groups.

2. Description of the Prior Art

Interest in synthetic biodegradable polymers for the systemic deliveryof therapeutic agents began in the early 1970's with the work of Yolleset al., Polymer News 1, 9-15 (1970) using poly(lactic acid). Since thattime, numerous other polymers have been prepared and investigated asbioerodible matrices for the controlled release of therapeutic agents.

U.S. Pat. Nos. 4,079,038, 4,093,709, 4,131,648, 4,138,344 and 4,180,646disclose biodegradable or bioerodible polyorthoesters. These polymersare formed by a reaction between an orthoester (or orthocarbonate) suchas 2,2-diethoxytetrahydrofuran and a diol such as1,4-cyclohexanedimethanol. The reaction requires elevated temperatureand reduced pressure and a relatively long reaction time. Drugs or otheractive agents are retained in the polymer matrix to be released as thepolymer biodegrades due to hydrolysis of the labile linkages.

U.S. Pat. No. 4,304,767 discloses polymers prepared by reacting a polyolwith a polyfunctional ketene acetal. These polymers represent asignificant improvement over those of U.S. Pat. Nos. 4,079,038,4,093,709, 4,131,648, 4,138,344 and 4,180,646, since synthesis proceedsreadily at room temperature and atmospheric pressure, and the resultingpolymers have superior properties.

Further polymers are disclosed in U.S. Pat. No. 4,957,998. Thesepolymers contain acetal, carboxy-acetal and carboxy-orthoester linkages,and are prepared by a two-step process beginning with the reactionbetween a polyfunctional ketene acetal and a compound containing a vinylether, followed by reaction with a polyol or polyacid.

Still further polymers of a similar type are disclosed in U.S. Pat. No.4,946,931. The polymers are formed by a reaction between a compoundcontaining a multiplicity of carboxylate functions and a polyfunctionalketene acetal. The resulting polymers have very rapid erosion times.

Despite the ease with which the orthoester linkage hydrolyses,polyorthoesters known in the prior art are extremely stable materialswhen placed in an aqueous buffer, or when residing in the body. Thisstability is attributable to the extreme hydrophobicity of thepolyorthoesters which severely limits the amount of water that canpenetrate the polymer. To achieve useful erosion rates, therefore,acidic excipients must be physically incorporated into the polymer.While this allows control over erosion rates, the physicallyincorporated acidic excipient can diffuse from the polymer matrix atvarying rates, leaving a matrix that is completely depleted of excipientwhile the polymer still has a very long lifetime remaining.

U.S. Pat. No. 5,968,543 (Heller et al.) describes polyorthoesterscontaining α-hydroxy acid-containing groups. The polyorthoesters areformed from the reaction of a diketene acetal such as3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU) with atleast 0.1 mol % of an “α-hydroxy acid” diol and 0-99.9 mol % of one ormore of a “hard” diol and a “soft” diol (as those terms are used in thepatent). These polyorthoesters are stated to have greater bioerodibilitythan similar polyorthoesters not containing the α-hydroxy acidester-containing groups, and to have the bioerodibility controllable byvariation in the concentration of the α-hydroxy acid ester-containinggroups.

U.S. Pat. No. 4,549,010 (Sparer et al.) describes polyorthoesterscontaining functional groups which produce hydrogen bonding.

The disclosures of the documents listed in this section and elsewherethroughout this application are incorporated herein by reference.

SUMMARY OF THE INVENTION

In a first aspect, this invention is polyorthoesters of formula I:

where:

R is a bond, —(CH₂)_(a)—, or —(CH₂)_(a)—O—(CH₂)_(a)—; where A is aninteger of 1 to 10, and b and c are independently integers of 1 to 5;

R* is a C₁₋₄ alkyl;

n is an integer of at least 5; and

A is R¹, R², R³, or R⁴, where

R¹ is:

where:

p is an integer of 1 to 20;

R⁵ is hydrogen or C₁₋₄ alkyl; and

R⁶ is:

where:

s is an integer of 0 to 30;

t is an integer of 2 to 200; and

R⁷ is hydrogen or C₁₋₄ alkyl;

R² is:

R³ is:

where:

x is an integer of 0 to 30;

y is an integer of 2 to 200;

R⁸ is hydrogen or C₁₋₄ alkyl;

R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene;

R¹¹ is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆ alkyl; or R¹¹ and R¹²together are C₃₋₁₀ alkylene; and

R⁴ is the residue of a diol containing at least one functional groupindependently selected from amide, imide, urea, and urethane groups;

in which at least 0.1 mol % of the A units are R¹.

In a second aspect, this invention is controlled release pharmaceuticalcompositions comprising:

(a) an active agent; and

(b) as a vehicle, the polyorthoester described above.

In a third aspect, this invention is a method of treating a diseasestate treatable by controlled release local administration of an activeagent, in particular treating pain by administration of a localanesthetic or treating cancer by administration of a chemotherapeutic orantineoplastic agent, comprising locally administering a therapeuticallyeffective amount of the active agent in the form of the pharmaceuticalcomposition described above.

In a fourth aspect, this invention is methods of using thepolyorthoesters of the first aspect of the invention as bioerodibleimplants.

In a fifth aspect, this invention is methods of preparation of thepolyorthoesters of the first aspect of the invention and the controlledrelease pharmaceutical compositions of the second aspect of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

It has now been discovered that polyorthoesters useful as orthopedicimplants or vehicles for the sequestration and sustained delivery ofdrugs, cosmetic agents and other beneficial agents can be prepared insuch a manner that the rate and degree to which they are hydrolyzed bycontact with bodily fluids at normal body temperature and pH can becontrolled without addition of exogenous acid. This discovery resides inthe incorporation of esters of short-chain α-hydroxy acids such asesters of glycolic acid, lactic acid or glycolic-co-lactic acidcopolymer into the polyorthoester chain and variation of the amount ofthese esters relative to the polyorthoester as a whole.

In the presence of water, these esters, when incorporated into thepolyorthoester chain, are readily hydrolyzed at a body temperature of37° C. and a physiological pH, in particular at a pH of 7.4, to producethe corresponding α-hydroxy acids. The α-hydroxy acids then act as anacidic excipient to control the hydrolysis rate of the polyorthoester.When the polyorthoester is used as a vehicle or matrix entrapping anactive agent, the hydrolysis of the polyorthoester causes release of theactive agent.

In addition, the mechano-physical state of the polyorthoester may alsobe controlled. This is achieved by the inclusion of the residues ofcertain diols in selected proportions relative to the polyorthoester asa whole. For example, a high content of the residue oftrans-1,4-cyclohexane-dimethanol or a similar “hard” diol relative to a“soft” diol (definition of which is given below) produces a relativelyrigid polymer chain and a more solid substance, and by decreasing thetrans-cyclohexanedimethanol content relative to the “soft” diol, thepolyorthoester will change progressively through the stages of a rigidthermoplastic, a soft thermoplastic, a low melting solid to anointment-like (viscous liquid) material, and any stage in between.

The polyorthoesters of the present invention are prepared bycondensation reactions between diketene acetals and polyols, preferablydiols, and the variation in mechano-physical state and rate ofhydrolysis (bioerodibility) is achieved by the selection and use ofcombinations of different types of diols.

Definitions

“Active agent” includes any compound or mixture of compounds whichproduces a beneficial or useful result. Active agents aredistinguishable from such components as vehicles, carriers, diluents,lubricants, binders and other formulating aids, and encapsulating orotherwise protective components. Examples of active agents arepharmaceutical, agricultural or cosmetic agents. Suitable pharmaceuticalagents include locally or systemically acting pharmaceutically activeagents which may be administered to a subject by topical orintralesional application (including, for example, applying to abradedskin, lacerations, puncture wounds, etc., as well as into surgicalincisions) or by injection, such as subcutaneous, intradermal,intramuscular, intraocular, or intra-articular injection. Examples ofthese agents include, but not limited to, anti-infectives (includingantibiotics, antivirals, fungicides, scabicides or pediculicides),antiseptics (e.g., benzalkonium chloride, benzethonium chloride,chlorhexidine gluconate, mafenide acetate, methylbenzethonium chloride,nitrofurazone, nitromersol and the like), steroids (e.g., estrogens,progestins, androgens, adrenocorticoids, and the like), therapeuticpolypeptides (e.g. insulin, erythropoietin, morphogenic proteins such asbone morphogenic protein, and the like), analgesics andanti-inflammatory agents (e.g., aspirin, ibuprofen, naproxen, ketorolac,COX-1 inhibitors, COX-2 inhibitors, and the like), cancerchemotherapeutic agents (e.g., mechlorethamine, cyclophosphamide,fluorouracil, thioguanine, carmustine, lomustine, melphalan,chlorambucil, streptozocin, methotrexate, vincristine, bleomycin,vinblastine, vindesine, dactinomycin, daunorubicin, doxorubicin,tamoxifen, and the like), narcotics (e.g., morphine, meperidine,codeine, and the like), local anesthetics (e.g., the amide- oranilide-type local anesthetics such as bupivacaine, dibucaine,mepivacaine, procaine, lidocaine, tetracaine, and the like),antiangiogenic agents (e.g., combrestatin, contortrostatin, anti-VEGF,and the like), polysaccharides, vaccines, antigens, DNA and otherpolynucleotides, antisense oligonucleotides, and the like. The presentinvention may also be applied to other locally acting active agents,such as astringents, antiperspirants, irritants, rubefacients,vesicants, sclerosing agents, caustics, escharotics, keratolytic agents,sunscreens and a variety of dermatologics including hypopigmenting andantipruritic agents. The term “active agents” further includes biocidessuch as fungicides, pesticides, and herbicides, plant growth promotersor inhibitors, preservatives, disinfectants, air purifiers andnutrients.

“Alkyl” denotes a linear saturated hydrocarbyl having from one to thenumber of carbon atoms designated, or a branched or cyclic saturatedhydrocarbyl having from three to the number of carbon atoms designated(e.g., C₁₋₄ alkyl). Examples of alkyl include methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, t-butyl, cyclopropylmethyl, and thelike.

“Alkylene” denotes a branched or unbranched saturated divalent radicalhaving from one to the number of carbon atoms designated (e.g., C₁-C₁₂alkylene). Examples of alkylene include methylene (—CH₂—), ethylene(—CH₂CH₂—), isopentylene (—CH₂—CH(CH₃)—CH₂—CH₂—), n-octylene (—(CH₂)₈—)and the like.

“Bioerodible” and “bioerodibility” refer to the degradation, disassemblyor digestion of the polyorthoester by action of a biologicalenvironment, including the action of living organisms and most notablyat physiological pH and temperature. A principal mechanism forbioerosion of the polyorthoesters of the present invention is hydrolysisof linkages between and within the units of the polyorthoester.

“Comprising” is an inclusive term interpreted to mean containing,embracing, covering or including the elements listed following the term,but not excluding other unrecited elements.

“Controlled release”, “sustained release”, and similar terms are used todenote a mode of active agent delivery that occurs when the active agentis released from the delivery vehicle at an ascertainable andcontrollable rate over a period of time, rather than dispersedimmediately upon application or injection. Controlled or sustainedrelease may extend for hours, days or months, and may vary as a functionof numerous factors. For the pharmaceutical composition of the presentinvention, the rate of release will depend on the type of the excipientselected and the concentration of the excipient in the composition.Another determinant of the rate of release is the rate of hydrolysis ofthe linkages between and within the units of the polyorthoester. Therate of hydrolysis in turn may be controlled by the composition of thepolyorthoester and the number of hydrolyzable bonds in thepolyorthoester. Other factors determining the rate of release of anactive agent from the present pharmaceutical composition includeparticle size, acidity of the medium (either internal or external to thematrix) and physical and chemical properties of the active agent in thematrix.

“Matrix” denotes the physical structure of the polyorthoester whichessentially retains the active agent in a manner preventing release ofthe agent until the polyorthoester erodes or decomposes.

“Sequestration” is the confinement or retention of an active agentwithin the internal spaces of a polyorthoester matrix. Sequestration ofan active agent within the matrix may limit the toxic effect of theagent, prolong the time of action of the agent in a controlled manner,permit the release of the agent in a precisely defined location in anorganism, or protect unstable agents against the action of theenvironment.

A “therapeutically effective amount” means the amount that, whenadministered to an animal for treating a disease, is sufficient toeffect treatment for that disease.

“Treating” or “treatment” of a disease includes preventing the diseasefrom occurring in an animal that may be predisposed to the disease butdoes not yet experience or exhibit symptoms of the disease (prophylactictreatment), inhibiting the disease (slowing or arresting itsdevelopment), providing relief from the symptoms or side-effects of thedisease (including palliative treatment), and relieving the disease(causing regression of the disease). For the purposes of this invention,a “disease” includes pain.

A “unit” denotes an individual segment of a polyorthoester chain, whichconsists of the residue of a diketene acetal molecule and the residue ofa polyol.

An “α-hydroxy acid containing” unit denotes a unit where A is R¹, i.e.in which the polyol is prepared from an α-hydroxy acid or cyclic diesterthereof and a diol of the formula HO—R⁶—OH. The fraction of thepolyorthoester that is α-hydroxy acid containing units affects the rateof hydrolysis (or bioerodibility) of the polyorthoester, and in turn,the release rate of the active agent.

“Hard”, “soft”, and “hydrogen bonding” units denote individual units ofthe polyorthoester, the contents of which relative to the polyorthoesteras a whole determine the mechano-physical state of the polyorthoester.“Hard” units are units where A is R², “soft” units are units where A isR³, and “hydrogen bonding” units are units where A is R⁴.

“Vehicle” and “carrier” denote an ingredient that is included in acomposition such as a pharmaceutical or cosmetic preparation for reasonsother than a therapeutic or other biological effect. Functions served byvehicles and carriers include transporting an active agent to a site ofinterest, controlling the rate of access to, or release of, the activeagent by sequestration or other means, and facilitating the applicationof the agent to the region where its activity is needed.

The polyorthoesters are of formula I:

where:

R is a bond, —(CH₂)_(a)—, or —(CH₂)_(a)—O—(CH₂)_(a)—; where a is aninteger of 1 to 10, and b and c are independently integers of 1 to 5;

R* is a C₁₋₄alkyl;

n is an integer of at least 5; and

A is R¹, R², R³, or R⁴, where

R¹ is:

where:

p is an integer of 1 to 20;

R⁵ is hydrogen or C₁₋₄ alkyl; and

R⁶ is:

where:

s is an integer of 0 to 30;

t is an integer of 2 to 200; and

R⁷ is hydrogen or C₁₋₄ alkyl;

R² is:

R³ is:

where:

x is an integer of 0 to 30;

y is an integer of 2 to 200;

R⁸ is hydrogen or C₁₋₄ alkyl;

R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene;

R¹¹ is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆alkyl; or R¹¹ and R¹²together are C₃₋₁₀ alkylene; and

R⁴ is the residue of a diol containing at least one functional groupindependently selected from amide, imide, urea, and urethane groups;

in which at least 0.1 mol % of the A units are R¹.

The structure of the polyorthoester of the present invention, as shownin formula I, is one of alternating residues of a diketene acetal and adiol, with each adjacent pair of diketene acetal residues beingseparated by the residue of one polyol, preferably a diol.

In the presence of water, the α-hydroxyacid containing units are readilyhydrolyzed at a body temperature of 37° C. and a physiological pH, toproduce the corresponding hydroxyacids. These hydroxyacids then act asacidic catalysts to control the hydrolysis rate of the polyorthoesterwithout the addition of exogenous acid. When the polyorthoester is usedas a delivery vehicle or matrix entrapping an active agent, thehydrolysis of the polyorthoester causes release of the active agent.

Polyorthoesters having a higher mole percentage of the “α-hydroxy acidcontaining” units will have a higher rate of bioerodibility. Preferredpolyorthoesters are those in which the mole percentage of the “α-hydroxyacid containing” units is in the range of about 1 to about 50 molepercent, more preferably from about 2 to about 30 mole percent, forexample from about 5 to about 30 mole percent, especially from about 10to about 30 mole percent.

Preferred polyorthoesters are those where:

n is an integer of 5 to 1000;

R⁵ is hydrogen or methyl;

R⁶ is:

 where s is an integer of 0 to 10, especially 1 to 4; s is an integer of2 to 30, especially 2 to 10; and R⁷ is hydrogen or methyl;

R³ is:

 where x is an integer of 0 to 10, especially 1 to 4; y is an integer of2 to 30, especially 2 to 10; and R⁸ is hydrogen or methyl;

R⁴ is selected from the residues of aliphatic diols of 2 to 20 carbonatoms, preferably 2 to 10 carbon atoms, interrupted by one amide, imide,urea, or urethane group; and

the proportion of units in which A is R¹ is 1-50 mol %, preferably 2-30mol %, more preferably 5-30 mol %.

While the presence of any of these preferences results in apolyorthoester that is more preferred than the same polyorthoester inwhich the preference is not met, the preferences are generallyindependent, and polyorthoesters in which a greater number ofpreferences is met will generally result in a polyorthoester that ismore preferred than that in which a lesser number of preferences is met.

Expressed in terms of mole percent of the “hard” or “hydrogen bonding”unit relative to the polyorthoester as a whole, preferredpolyorthoesters for liquid or ointment-like compositions are those inwhich the “hard” or “hydrogen bonding” unit constitutes about 20 molepercent or less. Likewise, preferred polyorthoesters for more solidcompositions are those in which the “hard” or “hydrogen bonding” unitconstitutes from about 60 mole percent to about 99.9 mole percent.

Polyorthoesters having a higher content of the “α-hydroxy acidcontaining” unit will have a higher rate of bioerodibility. Preferredpolyorthoesters are those in which the “α-hydroxy acid containing” unitsconstitute preferably from about 1 to about 50 mole percent, morepreferably from about 2 to about 30 mole percent, for example from about5 to about 30 mole percent, especially from about 10 to about 30 molepercent.

With respect to the individual “α-hydroxy acid containing” unit, p ispreferably 1 to 6, more preferably 1 to 4, most preferably 1 or 2; R⁵ ispreferably hydrogen or methyl; and in the above definitions of R⁶, s ispreferably 2 to 12, more preferably 2 to 6 and most preferably 2; and tis preferably 4 to 12, more preferably 4 to 6 and most preferably 6.

With respect to the individual “hard” unit, HO—R²—OH is preferablytrans-cyclohexanedimethanol.

With respect to the individual “soft” unit, in the definitions of R³, xis preferably 2 to 12, more preferably 2 to 6 and most preferably 2; yis preferably 4 to 12, more preferably 4 to 6 and most preferably 6; R⁸is preferably hydrogen; R⁹ and R¹⁰ are preferably identical, morepreferably an unbranched C₄-C₁₂ alkylene and most preferably anunbranched C₆-C₁₂ alkylene; R¹¹ is preferably hydrogen, and R¹² ispreferably methyl.

Preparation of the Polyorthoesters

The polyorthoesters are prepared according to the methods described inU.S. Pat. Nos. 4,549,010 and 5,968,543. Specifically, thepolyorthoesters are prepared by the reaction of a diketene acetal offormula II:

where L is hydrogen or a C₁₋₃ alkyl, with a diol of the formulaHO—R¹—OH, and optionally at least one diol of the formulae HO—R²—OH,HO—R³—OH, and HO—R⁴—OH.

The rigidity or flexibility of the polyorthoester is determined by theproportions of the “hard” and “hydrogen bonding” units and “soft” unitsin the polyorthoester structure, with greater rigidity achieved byincluding greater proportions of the “hard” and “hydrogen bonding” unitsin the polyorthoester.

The bioerodibility of the polyorthoester is determined by the proportionof the hydrolyzable α-hydroxy acid ester groups, with greaterbioerodibility achieved by including greater proportions of the“α-hydroxy acid containing” units.

Thus, both characteristics of the resulting polyorthoester prepared fromthe reaction between the diketene acetal of Formula II and a mixture ofthe diols, are controlled by the ratio of quantities of the two to fourtypes of diols in the diol mixture.

It is also understood that the present invention encompassescross-linked polyorthoesters which are prepared by employing one or morepolyols having more than two hydroxy functional groups. Suchcross-linked polyorthoesters may be prepared preferably by firstreacting the diketene acetal with a mixture of diols comprising a diolof the formula HO—R¹—OH and optionally at least one diol of the formulaHO—R²—OH, HO—R³—OH, and HO—R⁴—OH, followed by addition of the polyol(s)having more than two hydroxy functional groups. Alternatively, thepolyol(s) having more than two hydroxy functional groups may be addedsimultaneously with the diol of the formula HO—R¹—OH and other diols.Polyols having more than two hydroxy functional groups suitable for thepreparation of the cross-linked polyorthoesters may be the straight orbranched chain type, including polyhydroxyl compounds such as1,2,3-propanetriol, 1,2,5-pentanetriol, 1,2,6-hexanetriol,1,3,5-pentanetriol, 1,2,4-butanetriol, 1,4,7-heptanetriol,1,5,10-decanetriol, 1,5,12-dodecanetriol, 1,2,3,4,5,6-hexane-hexol andthe like. Other representative polyols of the type are described in U.S.Pat. No. 4,304,767. The reaction conditions (e.g., suitable solvents andreaction temperatures) and procedures for the preparation of thecross-linked polyorthoesters are similar to those described above forthe preparation of the polyorthoesters employing only the diols, and arealso described in U.S. Pat. Nos. 4,304,767 and 5,968,543.

The preparation of the diketene acetals of formula II is disclosed inCrivello et al., J. Polymer Sci., Part A: Polymer Chemistry, 34,3091-3102 (1996); and will be known to a person of ordinary skill in theart. A typical method is the condensation of a bis(diol) of formula III:

with two equivalents of a 2-halocarboxaldehyde dialkyl acetal, such as2-bromoacetaldehyde diethyl acetal, followed by dehydrohalogenation togive the diketene acetal. The condensation of a glycol withdiethylbromoacetals is described in Roberts et al., J. Am. Chem. Soc.,80, 1247-1254 (1958), and dehydrohalogenation is described in Beyerstedtet al., J. Am. Chem. Soc., 58, 529-553 (1936).

The diketene acetals may also be prepared by the isomerization ofdivinyl acetals. The isomerization of the double bond is described inCorey et al., J. Org. Chem., 38, 3224 (1973). The divinyl acetals may beprepared by the condensation of the bis(diol) of formula III with twoequivalents of a vinylic aldehyde, such as acrolein or crotonaldehyde,or their dialkyl acetals, such as acrolein dimethyl acetal, and suchcondensation reactions are well known. Thus, for example,2,2′-divinyl-4,4′-bis(1,3-dioxolane) is prepared from the reaction oferythritol with acrolein in benzene/p-toluenesulfonic acid; and issubsequently isomerized to 2,2′-diethylidene-4,4′-bis(1,3-dioxolane)with tris(triphenylphosphine)ruthenium(II) chloride.

The bis(diol) of formula III where R is a bond is erythritol. Thebis(diol) of formula III where R is —(CH₂)_(a)— may be prepared by theoxidation of an α,ω-diene, such as 1,3-butadiene or 1,5-hexadiene, withan oxidizing reagent such as osmium tetroxide/hydrogen peroxide, or byother methods known in the art, to give the bis(diol). The bis(diol) offormula III where R is —(CH₂)_(b)—O—(CH₂)_(c)— may be prepared by thereaction of an ω-hydroxy-α-olefin, such as allyl alcohol, with anω-haloalkyloxirane, such as epichlorohydrin, to form an ω-epoxy-α-olefinwith the backbone interrupted by an oxygen atom, such as2-allyloxymethyloxirane, which is then oxidized with an oxidizingreagent such as osmium tetroxide/hydrogen peroxide, or by other methodsknown in the art, to give the bis(diol).

The diols of the formulae HO—R¹—OH, HO—R²—OH, HO—R³—OH, and HO—R⁴—OH areprepared according to methods known in the art, and as described, forexample, in U.S. Pat. Nos. 4,549,010 and 5,968,543. Some of the diolsare commercially available. The diol of the formula HO—R¹—OH thatcomprises a polyester moiety may be prepared by reacting a diol of theformula HO—R⁶—OH with between 0.5 and 10 molar equivalents of a cyclicdiester of an α-hydroxy acid, such as lactide or glycolide, and allowingthe reaction to proceed at 100-200° C. for about 12 hours to about 48hours. Although particular solvents are not required for this reaction,organic solvents such as dimethylacetamide, dimethyl sulfoxide,dimethylformamide, acetonitrile, pyrrolidone, tetrahydrofuran, andmethylbutyl ether may be used. The preparation of diols, in particularthe diol of the formula HO—R³—OH is generally disclosed in Heller etal., J. Polymer Sci., Polymer Letters Ed., 18, 293-297 (1980), byreacting an appropriate divinyl ether with an excess of an appropriatediol. Diols of the formula HO—R⁴—OH include diols where R⁴ is R′CONR″R′(amide), R′CONR″COR′ (imide), R′NR″CONR″R′ (urea), and R′OCONR″R′(urethane), where each R′ is independently an aliphatic, aromatic, oraromatic/aliphatic straight or branched chain hydrocarbyl, especially astraight or branched chain alkyl of 2 to 22 carbon atoms, especially 2to 10 carbon atoms, and more especially 2 to 5 carbon atoms, and R″ ishydrogen or C₁₋₆ alkyl, especially hydrogen or methyl, more especiallyhydrogen. Some representative diols of the formula HO—R⁴—OH includeN,N′-bis-(2-hydroxyethyl)terephthalamide,N,N′-bis-(2-hydroxyethyl)pyromellitic diimide,1,1′-methylenedi(p-phenylene)-bis-[3-(2-hydroxyethyl)urea],N,N′-bis-(2-hydroxyethyl)oxamide, 1,3-bis(2-hydroxyethyl)urea,3-hydroxy-N-(2-hydroxyethyl)propionamide,4-hydroxy-N-(3-hydroxypropyl)butyramide, andbis(2-hydroxyethyl)ethylenedicarbamate. These diols are known to the artin reported syntheses and may are commercially available. Representativediols of the formula HO—(CH₂)_(n)—NHCO—(CH₂)_(m)—OH where n is aninteger of 2 to 6 and m is an integer of 2 to 5 are made by the reactionof 2-aminoethanol, 3-aminopropanol, 4-aminobutanol, 5-aminopentanol, or6-aminohexanol with β-propiolactone, γ-butyrolactone, δ-valerolactone,or ε-caprolactone. Representative diols of the formulaHO—(CH₂)_(n)—NHCOO—(CH₂)_(m)—OH where n and m are each integers of 2 to6 are made by the reaction of the same aminoalcohols just mentioned withcyclic carbonates of the formula

such as ethylene carbonate. Bis-amide diols of the formulaHO—A—NHCO—B—CONH—A—OH are prepared by the reaction of a diacid,optionally in activated form, such as the diacyldihalide, with twoequivalents of a hydroxy-amine. Other methods of preparation of thediols of the formula HO—R⁴—OH are known in the art.

Once made, the diol of the formula HO—R¹—OH, and the diol(s) of theformulae HO—R²—OH, HO—R³—OH, and HO—R⁴—OH in the desired proportions aremixed with the diketene acetal of formula II, typically in a slightlyless than 1:1 (e.g. 0.5:1-0.9:1) ratio of total number of moles ofdiketene acetal to total number of moles of diols, in a suitable solventat ambient temperature. The condensation reaction between the diketeneacetal and the diols is carried out under conditions which are describedin, for example, U.S. Pat. Nos. 4,304,767, 4,549,010, and 5,968,543, andare well known to those skilled in the art; and will also be readilyapparent from the structures of the reactants themselves. Suitablesolvents are aprotic solvents, such as dimethylacetamide, dimethylsulfoxide, dimethylformamide, acetonitrile, acetone, ethyl acetate,pyrrolidone, tetrahydrofuran, and methylbutyl ether, and the like.Catalysts are not required for this reaction, but when used, suitablecatalysts are iodine in pyridine, p-toluenesulfonic acid; salicylicacid, Lewis acids (such as boron trichloride, boron trifluoride, borontrichloride etherate, boron trifluoride etherate, stannic oxychloride,phosphorous oxychloride, zinc chloride, phosphorus pentachloride,antimony pentafluoride, stannous octoate, stannic chloride, diethylzinc, and mixtures thereof); and Brønsted catalysts (such aspolyphosphoric acid, crosslinked polystyrene sulfonic acid, acidicsilica gel, and mixtures thereof). A typical amount of catalyst used isabout 0.2% by weight relative to the diketene acetal. Smaller or largeramounts can also be used, such as 0.005% to about 2.0% by weightrelative to the diketene acetal. Once the reaction is complete, thereaction mixture is allowed to cool and concentrated by rotoevaporationunder vacuum. The concentrated mixture may be further dried under vacuumat an elevated temperature.

The polyorthoesters may also be prepared by reaction of the diketeneacetal with the chosen diol(s) under similar reaction conditions, but inthe presence of a “chain stopper” (a reagent that terminatespolyorthoester chain formation). Suitable chain stoppers are C₅₋₂₀alkanols, especially C₁₀₋₂₀ alkanols. The chain stopper is preferablypresent in from 1-20 mol % based on the diketene acetal. Thepolyorthoesters thus prepared have lower molecular weights with a lowermolecular weight dispersion than those prepared by the reaction of thediketene acetals with only diols.

It is also understood that the present invention encompassescross-linked polymers which are prepared by employing one or morepolyols having more than two hydroxy functional groups. Suchcross-linked polymers may be prepared preferably by first reacting thediketene acetal with a mixture of diols comprising a diol of the formulaHO—R¹—OH and optionally diols of the formulae HO—R²—OH, HO—R³—OH, and/orHO—R⁴—OH followed by addition of the polyol(s) having more than twohydroxy functional groups. Alternatively, the polyol(s) having more thantwo hydroxy functional groups may be added simultaneously with the diolof the formula HO—R¹—OH and other diols. Polyols having more than twohydroxy functional groups suitable for the preparation of thecross-linked polymers may be the straight or branched chain type,including polyhydroxyl compounds such as 1,2,3-propanetriol,1,2,5-pentanetriol, 1,2,6-hexanetriol, 1,3,5-peiitanetriol,1,2,4-butanetriol, 1,4,7-heptanetriol, 1,5,10-decanetriol,1,5,12-dodecanetriol, 1,2,3,4,5,6-hexane-hexol and the like. Otherrepresentative polyols of the type are described in U.S. Pat. No.4,304,767. The reaction conditions (e.g., suitable solvents and reactiontemperatures) and procedures for the preparation of the cross-linkedpolymers are similar to those described above for the preparation of thepolymers employing only the diols, and are also described in U.S. Pat.No. 4,304,767.

The invention includes polyorthoesters which contain all four types ofunits as well as polyorthoesters containing from only the “α-hydroxyacid containing” units, or a mixture of these units with only one or twoof the “hard”, “soft”, and “hydrogen bonding” units. It also includespolyorthoesters prepared from a mixture of units which contains two ormore diols of the same type.

Uses of the Polyorthoesters

The present polyorthoesters can be used for any use in which bioerodiblepolymers are usable, such as vehicles for the sustained release of anactive agent or as orthopedic implants.

To use the polyorthoester as a sustained-release vehicle, the activeagent must be incorporated into a matrix of the polyorthoester orencapsulated within a capsule (or a “microcapsule” or “nanocapsule”, asthose terms are sometimes used) of the polyorthoester. Methods for thepreparation of sustained-release dosage forms using biodegradablepolymers are well known in the art, as discussed in the references citedin the “Description of the Prior Art” section of this application, andin other references familiar to those of ordinary skill in the art; sothat a person of ordinary skill in the art would have no difficulty,having regard to that skill and this disclosure, in preparingsustained-release formulations using the polyorthoester of thisinvention. Suitable active agents include therapeutic agents such aspharmaceutical or pharmacological active agents, e.g. drugs andmedicaments, as well as prophylactic agents, diagnostic agents, andother chemicals or materials useful in preventing or treating disease.The compositions of this invention are particularly useful for thetherapeutic treatment of humans and other mammals, but may also be usedfor other animals. In addition, the sustained-release compositions ofthis invention may also be used for the release of cosmetic andagricultural agents, or for the release of biocides, such as fungicidesor other pesticides, into an environment where prolonged release of theactive agent is desired.

In the case of matrix formulations, the polyorthoester is first mixedwith the active agent. High homogeneity may be achieved by mixing thepolyorthoester in its heat softened state with the active agent,followed by lowering the temperature to harden the composition.Alternatively, the polyorthoester can be dissolved in an appropriatecasting solvent, such as tetrahydrofuran, methylene chloride, chloroformor ethyl acetate, and the active agent can then be dispersed ordissolved in the polyorthoester solution, followed by evaporating thesolvent to achieve the finished composition. Another method is grindinga solid polyorthoester material into powder which is then mixed with apowdered active agent. The active agent may also be incorporated intothe mixture of monomers before polymerization provided that it is stableunder the polymerization conditions and does not interfere with thepolymerization reaction. If the active agent is one that is unstable atelevated temperatures (e.g. above 40° C.), or in the presence of organicsolvents or organic solvent/water mixtures, such as a protein, thenspecial preparation techniques may be required to minimize the exposureof the active agent to damaging conditions. Such techniques aredisclosed in, for example, U.S. Pat. Nos. 5,620,697 (Törmälä et al.,assigned to Orion-Yhtyma Oy and Leiras Oy), which discloses ultrasonicmelting to form matrix-type pharmaceutical compositions, and 5,518,730(Fuisz, assigned to Fuisz Technologies, Inc.), which disclosesmelt-spinning, both of which techniques are designed to minimize theexposure of the polymer and active to elevated temperatures. Othermethods are disclosed in the patents and literature references citedelsewhere in this application.

An alternate method for the incorporation and release of sensitivetherapeutic agents is to use bioerodible polyorthoesters that havephysical properties tailored for this incorporation. For example, thepolyorthoester may be chosen so that it is semi-solid and has anointment-like consistency, rather than being fully solid. Thus, apolyorthoester may be chosen that has a very high viscosity at normalbody temperature of 37° C. so that little if any deformation takes placeat that temperature. However, the viscosity of the polyorthoester maydecrease substantially at temperatures no higher than 45° C., orpreferably by 40° C., so that injection of the material may be possibleat a temperature at which the active agent retains its activity.

The composition obtained from any of the above methods can be readilyprocessed into a variety of shapes and forms for implantation, insertionor placement on the body or into body cavities or passageways. Forexample, the polyorthoester composition may be injection molded,extruded or compressed into a thin film or made into devices of variousgeometric shapes or forms such as flat, square, round, cylindrical,tubular, disc, ring and the like. Rod- or pellet-shaped devices may beimplanted through a trocar, such as is known for Norplant® implants, andthese or other shapes may be implanted by minor surgical procedures.Alternatively, a device may be implanted following a major surgicalprocedure such as tumor removal in the surgical treatment of cancer.

The polyorthoester composition may also be injected by syringesubcutaneously or intramuscularly as particles of 0.1μ to 1000μ,preferably 0.5μ to 200μ, and more preferably 1μ to 150μ suspended in apharmaceutically acceptable injection base. Liquid vehicles useful forsuspending the drug-polyorthoester composition for injection includeisotonic saline solution or oils (such as corn oil, cottonseed oil,peanut oil and sesame oil) which, if desired, may contain otheradjuvants.

Another injectable dosage form may be prepared from an active agentmixed in with a polyorthoester of the present invention which has anointment-like consistency. Such a dosage form may be administered byinjection with or without a solvent.

The polyorthoester composition administered by either injection orimplantation undergoes bioerosion in the body into non-toxic andnon-reactive materials. By controlling the number of hydrolyzable bondsin the polyorthoester, the active agent may be released at a desiredrate. Implants prepared from the present polyorthoesters in which thepolyorthoester constitutes the matrix containing an active agent alsohave the advantage that they do not require removal because of thebioerodibility of the polyorthoester.

In some cases, particles with cores of the pure active agent coated withvarious thicknesses of the present polyorthoester may be preferred forsustained delivery of the active agent. Coating or encapsulation ofdiscrete particles of the active agent may be accomplished byconventional methods which are all well-known to the person skilled inthe art. For example, finely divided drug particles may be suspended ina solvent system (in which the drug is not soluble) containing thedissolved polyorthoester and other excipients, followed by spray drying.Alternatively, the drug particles may be placed in a rotating pan or afluid-bed dryer and the polyorthoester dissolved in a carrier solvent issprayed onto the drug particles until a suitable coating quantity isdeposited on the particles to give a desired thickness. The coating mayalso be achieved by suspending the drug particles in a solvent systemcontaining the dissolved polyorthoester followed by adding to thesuspension a non-solvent causing the polyorthoester to precipitate andform a coating over the drug particles.

For the sustained release compositions, because the active agent will bereleased over a controlled period of time, the agent usually is presentin an amount which is greater than the conventional single dose. Therelative proportions of the active agent and the polyorthoester can varyover a wide range (e.g., 0.1 to 50 weight percent) depending on thetherapeutic agent and the desired effect.

Sustained compositions of cosmetic and agricultural agents may also beprepared by any one of the methods as described above, using thepolyorthoesters of the present invention.

The solid polyorthoesters (those containing a high percentage of the“hard” unit and/or a high proportion of the “hydrogen bonding” unit) arealso useful for a variety of orthopedic applications. For example, theycan be used as fracture fixation devices for repair of osteochondraldefects, ligament and tendon reconstructions and bone substitutes. Inaddition, the fact that the present polyorthoesters permit simultaneousselection of both a desired level of their mechano-physical state and adesired rate of bioerodibility, also renders them attractive as graftsor scaffolds on which cells can be cultured in vitro prior toimplantation to regenerate tissues. Tissues which can be regeneratedusing this approach include but not limited to, bone, tendon, cartilage,ligaments, liver, intestine, ureter and skin tissues. For example, thepolyorthoesters may be used to regenerate skin for patients with burnsor skin ulcers. Cartilages may be repaired by first isolatingchondrocytes from a patient (or a donor), allowing them to proliferateon the scaffolds prepared from the present polyorthoester andre-implanting the cells in the patient.

The polyorthoester scaffolds or implants may further contain otherbiologically active substances or synthetic inorganic materials such asreinforcing filler material for enhancing the mechanical properties ofthe scaffolds or implants (e.g. calcium sodium metaphosphate fibers),antibiotics or bone growth factors to induce and/or promote orthopedicrestoration and tissue regeneration.

The compositions are also stable. The release rates of the active agentare not affected by irradiation for sterilization.

Particular Compositions and their Uses

Exemplary compositions of this invention, and their uses, include:

(1) compositions containing local anesthetics, optionally in combinationwith glucocorticosteroids such as dexamethasone, cortisone,hydrocortisone, prednisone, prednisolone, beclomethasone, betamethasone,flunisolide, fluoconolone acetonide, fluocinonide, triamcinolone, andthe like, for the prolonged relief of local pain or a prolonged nerveblockade. This use is discussed further below;

(2) compositions containing cancer chemotherapeutic agents, such asthose listed above under “Active Agents”, for deposition by syringe orby injection into tumors or operative sites from which a tumor has beenablated, for tumor control or treatment and/or the suppression ofregrowth of the tumor from residual tumor cells after ablation of thetumor;

(3) compositions containing progestogens, such as flurogestone,medroxyprogesterone, norgestrel, norgestimate, norethindrone, and thelike, for estrus synchronization or contraception;

(4) compositions containing antimetabolites such as fluorouracil and thelike, as an adjunct to glaucoma filtering surgery; compositionscontaining antiangiogenic agents such as combrestatin, for the treatmentof macular degeneration and retinal angiogenesis; and other compositionsfor the controlled release of ophthalmic drugs to the eye;

(5) compositions containing therapeutic polypeptides (proteins), such asinsulin, LHRH antagonists, and the like, for the controlled delivery ofthese polypeptides, avoiding the need for daily or other frequentinjection;

(6) compositions containing anti-inflammatory agents such as the NSAIDs,e.g. ibuprofen, naproxen, COX-1 or COX-2 inhibitors, and the like, orglucocorticosteroids, for intra-articular injection;

(7) compositions containing antibiotics, for the prevention or treatmentof infection, especially for deposition into surgical sites to suppresspost-operative infection, or into or on wounds, for the suppression ofinfection (e.g. from foreign bodies in the wound);

(8) compositions containing morphogenic proteins such as bonemorphogenic protein; and

(9) compositions containing DNA or other polynucleotides, such asantisense oligonucleotides.

Delivery of Controlled-release Local Anesthetics by Injection

Local anesthetics induce a temporary nerve conduction block and providepain relief which lasts from a few minutes to a few hours. They arefrequently used to prevent pain in surgical procedures, dentalmanipulations or injuries.

The synthetic local anesthetics may be divided into two groups: theslightly soluble compounds and the soluble compounds. Conventionally,the soluble local anesthetics can be applied topically and by injection,and the slightly soluble local anesthetics are used only for surfaceapplication. The local anesthetics conventionally administered byinjection can also be divided into two groups, esters and non-esters.The esters include (1) benzoic acid esters (piperocaine, meprylcaine andisobucaine); (2) para-aminobenzoic acid esters (procaine, tetracaine,butethamine, propoxycaine, chloroprocaine); (3) meta-aminobenzoic acidesters (metabutethamine, primacaine); and (4) para-ethoxybenzoic acidester (parethoxycaine). The non-esters are anilides (amides ornonesters) which include bupivacaine, lidocaine, mepivacaine, pyrrocaineand prilocaine.

Many of the local anesthetics are conventionally used in the form oftheir acid addition salts, as this provides solubility in aqueousinjection media. However, because the presence of the large amount ofacid within such a local anesthetic acid addition salt will result inmore rapid degradation of the polyorthoesters and release of the localanesthetic, it is generally desirable to use the local anesthetics infree base form, or with only a small proportion of the acid additionsalt present (addition of small quantities of the acid addition salt mayprovide enhanced release if desired).

The semi-solid injectable form of a local anesthetic of the presentinvention is prepared by incorporating the local anesthetic into thedelivery vehicle in a manner as described above. The concentration ofthe local anesthetic may vary from 1-60 wt. %, preferably 5-30 wt. %,e.g. about 10 wt. %. The semi-solid composition is then filled into asyringe with a 18-25 gauge needle, and injected into sites that arepainful or to be subjected to surgical procedures. The semi-solidinjectable composition of the present invention can be used forcontrolled delivery of both slightly soluble and soluble localanesthetics.

Because the duration of action of a local anesthetic is proportional tothe time during which it is in actual contact with nervous tissues, thepresent injectable delivery system can maintain localization of theanesthetic at the nerve for an extended period of time which willgreatly prolong the effect of the anesthetic.

A number of authors, including Berde et al., U.S. Pat. No. 6,046,187 andrelated patents, have suggested that the co-administration of aglucocorticosteroid may prolong or otherwise enhance the effect of localanesthetics, especially controlled-release local anesthetics; andformulations containing a local anesthetic and a glucocorticosteroid,and their uses for controlled release local anesthesia, are within thescope of this invention.

EXAMPLE

The following synthesis illustrates the preparation of a polyorthoesterof this invention.

The polyorthoester in this example is prepared from2,2′-diethylidene-4,4′-bis(1,3-dioxolane), a diol of formula IV:

trans-cyclohexanedimethanol (t-CDM), andN,N′-bis(2-hydroxyethyl)oxamide. The molar ratio of the four components(2,2′-diethylidene-4,4′-bis(1,3-dioxolane):diol of formulaIV:t-CDM:N,N′-bis(2-hydroxyethyl)oxamide is 100:9:90:1.

2,2′-Diethylidene-4,4′-bis(1,3-dioxolane) is prepared as described inCrivello et al., referred to above; the diol of formula IV is preparedas described in U.S. Pat. No. 5,968,543; and t-CDM andN,N′-bis(2-hydroxyethyl)oxamide are obtained commercially.

Under rigorously anhydrous conditions,2,2′-diethylidene-4,4′-bis(1,3-dioxolane) (40 mmol), diol of formula IV(3.6 mmol), t-CDM (36 mmol), and4-hydroxy-N-(3-hydroxy-propyl)butyramide (0.4 mmol) are weighed into a250 mL round bottom flask, and the mixture dissolved in anhydroustetrahydrofuran (75 mL). To this solution is added a p-toluenesulfonicacid solution in tetrahydrofuran (5 drops, 40 mg/mL) to initiate thepolymerization. The solution comes to a boil within a few minutes. Thesolution is allowed to cool to room temperature, then is slowly pouredwith vigorous stirring into an excess of methanol (800 mL) containingtriethylamine (1 mL) as a stabilizer. The precipitated polyorthoester iscollected and dried overnight in a vacuum oven at 40° C.

The foregoing is offered primarily for purposes of illustration. It willbe readily apparent to those skilled in the art that the molecularstructures, proportions of the reactant materials, methods of use andother parameters of the invention described herein may be furthermodified or substituted in various ways without departing from thespirit and scope of the invention.

What is claimed is:
 1. A polyorthoester of formula I:

where: R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a isan integer of 1 to 10, and b and c are independently integers of 1 to 5;R* is a C₁₋₄ alkyl; n is an integer of at least 5; and A is R¹, R², R³,or R⁴, where R¹ is:

where: p is an integer of 1 to 20; R⁵ is hydrogen or C₁₋₄ alkyl; and R⁶is:

where: s is an integer of 0 to 30; t is an integer of 2 to 200; and R⁷is hydrogen or C₁₋₄ alkyl; R² is:

R³ is:

where: x is an integer of 0 to 30; y is an integer of 2 to 200; R⁸ ishydrogen or C₁₋₄ alkyl; R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene; R¹¹is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆ alkyl; or R¹¹ and R¹² togetherare C₃₋₁₀ alkylene; and R⁴ is the residue of a diol containing at leastone functional group independently selected from the group consisting ofamide, imide, urea, and urethane groups; in which at least 0.1 mol % ofthe A units are R¹.
 2. The polyorthoester of claim 1 where n is about 5to about
 1000. 3. The polyorthoester of claim 2 where n is about 20 toabout
 500. 4. The polyorthoester of claim 3 where n is about 30 to about300.
 5. The polyorthoester of claim 1 which comprises about 1 to about50 mole percent of units in which A is R¹.
 6. The polyorthoester ofclaim 5 which comprises about 2 to about 30 mole percent of units inwhich A is R¹.
 7. The polyorthoester of claim 6 which comprises about 5to about 30 mole percent of units in which A is R¹.
 8. Thepolyorthoester of claim 7 which comprises about 10 to about 30 molepercent of units in which A is R¹.
 9. The polyorthoester of claim 1where p is 1 to
 6. 10. The polyorthoester of claim 9 where p is 1 to 4.11. The polyorthoester of claim 10 where p is 1 to
 2. 12. Thepolyorthoester of claim 1 where R⁵ is hydrogen or methyl.
 13. Thepolyorthoester of claim 1 which comprises up to about 20 mole percent ofunits in which A is R².
 14. The polyorthoester of claim 1 whichcomprises about 60 to about 99.9 mole percent of units in which A is R².15. The polyorthoester of claim 1 where q is 1 to
 6. 16. Thepolyorthoester of claim 15 where q is 1 to
 3. 17. A process of preparinga polyorthoester of formula I:

where: R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a isan integer of 1 to 10, and b and c are independently integers of 1 to 5;R* is a C₁₋₄ alkyl; n is an integer of at least 5; and A is R¹, R², R³,or R⁴, where R¹ is:

where: p is an integer of 1 to 20; R⁵ is hydrogen or C₁₋₄ alkyl; and R⁶is:

where: s is an integer of 0 to 30; t is an integer of 2 to 200; and R⁷is hydrogen or C₁₋₄ alkyl; R² is:

R³ is:

where: x is an integer of 0 to 30; y is an integer of 2 to 200; R⁸ ishydrogen or C₁₋₄ alkyl; R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene; R¹¹is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆ alkyl; or R¹¹ and R¹² togetherare C₃₋₁₀ alkylene; and R⁴ is the residue of a diol containing at leastone functional group independently selected from the group consisting ofamide, imide, urea, and urethane groups; in which at least 0.1 mol % ofthe A units are R¹, the process comprising reacting a diketene acetal offormula II:

where L is hydrogen or a C₁₋₃ alkyl, with a diol of the formula HO—R¹—OH, and optionally at least one diol of the formulae HO—R²—OH, HO—R³—OH,and HO—R⁴—OH.
 18. A polyorthoester that is the product of a reactionbetween: (a) a diketene acetal of formula II:

where: R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a isan integer of 1 to 10, and b and c are independently integers of 1 to 5;and L is hydrogen or a C₁₋₃ alkyl, and (b) a polyol or mixture ofpolyols in which at least 0.1 mole percent of the total polyol contentis a diol of the formula HO—R¹—OH, where R¹ is:

where: p is an integer of 1 to 20; R⁵ is hydrogen or C₁₋₄ alkyl; and R⁶is:

where: s is an integer of 0 to 30; t is an integer of 2 to 200; and R⁷is hydrogen or C₁₋₄ alkyl;
 19. The polyorthoester of claim 18 where atleast one of the polyols is a polyol having more than two hydroxyfunctional groups.